Biology subjects

Krishnan, S.

Publications and source records attributed to Krishnan, S..

At least 55 records · Page 3Linked to original sources

bioRxiv2021

Reversal of the renal hyperglycemic memory by targeting sustained tubular p21 expression

A major therapeutic obstacle in diabetes mellitus is the metabolic or hyperglycemic memory: the persistence of impaired organ function despite improvement of blood glucose. Therapies reversing the hyperglycemic memory and thus improving already established organ-dysfunction are lacking, but urgently needed considering the increasing prevalence of diabetes mellitus worldwide. Here we show that glucose-mediated changes in gene expression largely persist in diabetic kidney disease (DKD) despite reversing hyperglycemia. The senescence-associated cyclin-dependent kinase inhibitor p21 (Cdkn1a) was the top hit among genes persistently induced by hyperglycemia and was associated with sustained induction of the p53-p21 pathway. Persistent p21 induction was confirmed in various animal models, in several independent human samples and in in vitro models. Tubular p21 expression and urinary p21-levels were associated with DKD severity and remained elevated despite improved blood glucose levels in humans, suggesting that p21 may be a biomarker indicating persistent ("memorized") kidney damage. Glucose-mediated p21 induction and tubular senescence were enhanced in mice with reduced levels of the disease resolving protease activated protein C (aPC). Mechanistically, glucose-induced and sustained tubular p21 expression is linked with demethylation of its promoter and reduced DNMT1 expression. aPC reverses already established p21 expression independent of its anticoagulant function through receptor signaling. Accordingly, new pharmacological approaches specifically mimicking aPC signaling (3K3A-aPC, parmodulin-2) enabled the reversal of glucose-mediated sustained tubular p21 expression, tubular senescence, and DKD. Thus, p21-dependent tubular senescence contributes to the hyperglycemic memory but can be therapeutically targeted. Single sentence summaryaPC signaling targets persistent p21 expression and tubular senescence and reverses the hyperglycemic memory in diabetic kidney disease.

molecular biology↗

bioRxiv2021

A Cryptochrome adopts distinct moon- and sunlight states and functions as moonlight interpreter in monthly oscillator entrainment

The moons monthly cycle synchronizes reproduction in countless marine organisms. The mass-spawning bristle worm Platynereis dumerilii uses an endogenous monthly oscillator to phase reproduction to specific days. Classical work showed that this oscillator is set by full moon. But how do organisms recognize such a specific moon phase? We uncover that the light receptor L-Cryptochrome (L-Cry) is able to discriminate between different moonlight durations, as well as between sun- and moonlight. Consistent with L-Crys function as light valence interpreter, its genetic loss leads to a faster re-entrainment under artificially strong nocturnal light. This suggests that L-Cry blocks "wrong" light from impacting on the monthly oscillator. A biochemical characterization of purified L-Cry protein, exposed to naturalistic sun- or moonlight, reveals the formation of distinct sun- and moonlight states characterized by different photoreduction- and recovery kinetics of L-Crys co-factor Flavin Adenine Dinucleotide. In vivo, L-Crys sun-versus moonlight states correlate with distinct sub-cellular localizations, indicating different signalling. In contrast, r-Opsin1, the most abundant ocular opsin, is not required for monthly oscillator entrainment. Our work reveals a new concept for correct moonlight interpretation involving a "valence interpreter" that provides entraining photoreceptor(s) with light source and moon phase information. These findings advance our mechanistic understanding of a fundamental biological phenomenon: moon-controlled monthly timing. Such level of understanding is also an essential prerequisite to tackle anthropogenic threats on marine ecology.

neuroscience↗

bioRxiv2021

Two light sensors decode moonlight versus sunlight to adjust a plastic circadian/circalunidian clock to moon phase

Many species synchronize their physiology and behavior to specific hours. It is commonly assumed that sunlight acts as the main entrainment signal for ~24h clocks. However, the moon provides similarly regular time information, and increasingly studies report correlations between diel behavior and lunidian cycles. Yet, mechanistic insight into the possible influences of the moon on ~24hr timers is scarce. We studied Platynereis dumerilii and uncover that the moon, besides its role in monthly timing, also schedules the exact hour of nocturnal swarming onset to the nights darkest times. Moonlight adjusts a plastic clock, exhibiting <24h (moonlit) or >24h (no moon) periodicity. Abundance, light sensitivity, and genetic requirement indicate Platynereis r-Opsin1 as receptor to determine moonrise, while the cryptochrome L-Cry is required to discriminate between moon- and sunlight valence. Comparative experiments in Drosophila suggest that Cryptochromes requirement for light valence interpretation is conserved. Its exact biochemical properties differ, however, between species with dissimilar timing ecology. Our work advances the molecular understanding of lunar impact on fundamental rhythmic processes, including those of marine mass spawners endangered by anthropogenic change.

neuroscience↗

bioRxiv2021

Implications of central carbon metabolism in SARS-CoV-2 replication and disease severity

Viruses hijack host metabolic pathways for their replicative advantage. Several observational trans-omics analyses associated carbon and amino acid metabolism in coronavirus disease 2019 (COVID-19) severity in patients but lacked mechanistic insights. In this study, using patient- derived multi-omics data and in vitro infection assays, we aimed to understand i) role of key metabolic pathways in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) reproduction and ii) its association with disease severity. Our data suggests that monocytes are key to the altered immune response during COVID-19. COVID-19 infection was associated with increased plasma glutamate levels, while glucose and mannose levels were determinants of the disease severity. Monocytes showed altered expression pattern of carbohydrate and amino acid transporters, GLUT1 and xCT respectively in severe COVID-19. Furthermore, lung epithelial cells (Calu-3) showed a strong acute metabolic adaptation following infection in vitro by modulating central carbon metabolism. We found that glycolysis and glutaminolysis are essential for virus replication and blocking these metabolic pathways caused significant reduction in virus production. Taken together, our study highlights that the virus utilizes and re-wires pathways governing central carbon metabolism leading to metabolic toxicity. Thus, the host metabolic perturbation could be an attractive strategy to limit the viral replication and disease severity.

microbiology↗

bioRxiv2020

An accurate aging clock developed from the largest dataset of microbial and human gene expression reveals molecular mechanisms of aging

Accurate measurement of the biological markers of the aging process could provide an "aging clock" measuring predicted longevity and allow for the quantification of the effects of specific lifestyle choices on healthy aging. Using modern machine learning techniques, we demonstrate that chronological age can be predicted accurately from (a) the expression level of human genes in capillary blood, and (b) the expression level of microbial genes in stool samples. The latter uses the largest existing metatranscriptomic dataset, stool samples from 90,303 individuals, and is the highest-performing gut microbiome-based aging model reported to date. Our analysis suggests associations between biological age and lifestyle/health factors, e.g., people on a paleo diet or with IBS tend to be biologically older, and people on a vegetarian diet tend to be biologically younger. We delineate the key pathways of systems-level biological decline based on the age-specific features of our model; targeting these mechanisms can aid in development of new anti-aging therapeutic strategies.

systems biology↗

bioRxiv2020

Changing reward expectation transforms spatial encoding and retrieval in the hippocampus

Internal states of reward expectation play a central role in influencing the strength of spatial memories. At the cellular level, spatial memories are represented through the firing dynamics of hippocampal place cells. However, it remains unclear how internal states of reward expectation influence place cell dynamics and exert their effects on spatial memories. Here we show that when reward expectation is altered, the same environment becomes encoded by a distinct ensemble of place cells at all locations. Further, when reward expectation is high versus low, place cells demonstrate enhanced reliability during navigation and greater stability across days at all locations within the environment. These findings reveal that when rewards are expected, neuromodulatory circuits that represent internal reward expectation support and strengthen the encoding and retrieval of spatial information by place cells at all locations that lead to reward. This enhanced spatial memory can be used to guide future decisions about which locations are most likely to lead to rewards that are crucial for survival.

neuroscience↗

bioRxiv2020

An fMRI study of initiation and inhibition of manual responses in people who stutter

Developmental stuttering is a speech motor disorder characterised by difficulties initiating speech and frequent interruptions to the speech flow. Previous work suggests that people who stutter (PWS) have an overactive response suppression mechanism. Imaging studies of speech production in PWS consistently reveal greater activity of the right inferior frontal cortex, an area robustly implicated in inhibitory control of both manual and spoken responses. Here, we used a manual response version of the stop-signal task during fMRI to investigate neural differences related to response initiation and inhibition in PWS. Behaviourally, PWS were slower to respond to go stimuli than people who are typically fluent (PWTF), but there was no difference in stop-signal reaction time. Our fMRI results were consistent with these behavioural results. The fMRI analysis revealed the expected networks associated with manual response initiation and inhibition in both groups. However, all contrasts between the two groups were characterised by overactivity in PWS relative to PWTF. This overactivity was significantly different for the initiation of responses (i.e. the go trials) but not for response inhibition (i.e. the stop trials). One explanation of these results is that PWS are consistently in a heightened inhibition state, i.e. areas of the inhibition network are more active, generally. This interpretation is consistent with predictions from the global response suppression hypothesis.

neuroscience↗

bioRxiv2020

Replication dynamics and cytotoxicity of SARS-CoV-2 Swedish isolate in commonly used laboratory cell lines

The present pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is driving intense research activities to understand the basic biology of the virus and determine effective therapeutic strategies. The commonly used laboratory cell lines of human origin are the first line of experimental models to study the pathogenicity and performing antiviral assays. Thus, to find suitable cell models to study SARS-CoV-2, we assessed the tropism and cytopathogenicity of the first Swedish isolate of SARS-CoV-2 in six different cell lines of human origin and compared their growth characteristics to other globally isolated strains. Overall, Calu-3, Caco2, Huh7, and 293FT cell lines showed a high to moderate level of susceptibility to the majority of virus isolates. In Caco2 cells the virus can achieve high titers in the absence of any prominent cytopathic effect. The protein expression profile during SARS-CoV-2 infection revealed cell-type-specific regulation of cellular pathways. Type-I interferon signaling was identified as the common dysregulated cellular response in Caco2, Calu-3 and Huh7 cells. Overall, cell-type specific variability was noted for cytopathogenicity, susceptibility and cellular response to SARS-CoV-2. This study provides important clues regarding SARS-CoV-2 pathogenesis and can represent as a guide for future studies to design therapeutics.

microbiology↗

bioRxiv2020

N-glycosylation network construction and analysis to modify glycans on the spike S glycoprotein of SARS-CoV-2.

Background The spike S-protein of SARS-CoV-2 is N-glycosylated. The N-glycan structure and composition of this glycoprotein influence how the virus interacts with host cells.Objective To identify a putative N-glycan biosynthesis pathway of SARS-CoV-2 (HEK293 cell recombinant) from previously published mass spectrometric studies, and to identify what effect blocking some enzymes has on the overall glycoprotein profile. Finally, our goal was to provide the biosynthesis network, and glycans in easy-to-use format for further glycoinformatics work.Methods We reconstructed the glycosylation network based on previously published empirical data using GNAT, a glycosylation network analysis tool. Our compilation of the network tool had 23 glycosyltransferase and glucosidase enzymes, and could infer the pathway of glycosylation machinery based on glycans identified in the virus spike protein. Once the glycan biosynthesis pathway was generated, we simulated the effect of blocking specific enzymes - Mannosidase-II and alpha-1,6-fucosyltransferase to see how they would affect the biosynthesis network.Results Of the 23 enzymes, a total of 12 were involved in glycosylation of SARS-CoV-2 - Man-Ia, MGAT1, MGAT2, MGAT4, MGAT5, B4GalT, B4GalT, Man II, SiaT, ST3GalI, ST3GalVI and FucT8. Blocking enzymes resulted in a substantially modified glycan profile of the protein.Conclusions A network analysis of N-glycan biosynthesis of SARS-CoV-2 spike protein shows an elaborate enzymatic pathway with several intermediate glycans, along with the ones identified by mass spectrometric studies. Variations in the final N-glycan profile of the virus, given its site-specific microheterogeneity, could be a factor in the host response to the infection and response to antibodies. Here we provide all the resources generated - the glycans derived from mass spectrometry and intermediate glycans in glycoCT xml format, and the biosynthesis network for future drug and vaccine development work.Competing Interest StatementThe authors have declared no competing interest.View Full Text

physiology↗

bioRxiv2020

Dysregulation in mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells

How Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remain largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected HuH7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a significant reduction in activated S6K1 and 4E-BP1 at 72 hours post infection. Unlike other human respiratory viruses, we found a significant inhibition of HIF-1 through the entire time course of the infection, suggesting a crosstalk between the SARS-CoV-2 and the mTOR/HIF-1 signaling. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe COVID-19 patients.

microbiology↗

bioRxiv2020

Larval zebrafish respond to the alarm pheromone Schreckstoff by immobility and a change in brain state

BackgroundDetection of predator cues changes the brain state in prey species and helps them avoid danger. Dysfunctionality in changing the central state appropriately in stressful situations is proposed to be an underlying cause of multiple psychiatric disorders in humans. MethodsHere, we investigate the dynamics of neural circuits mediating response to a threat, to characterize these states and to identify potential control networks. We use resonant scanning 2-photon microscopy for in vivo brain-wide imaging and custom designed behavioral assays for the study. ResultsWe first show that 5-7 day old zebrafish larvae react to an alarm pheromone (Schreckstoff) with reduced mobility. They subsequently display heightened vigilance, as evidenced by increased dark avoidance. Calcium imaging indicates that exposure to Schreckstoff elicits stimulus-locked activity in olfactory sensory neurons innervating a lateral glomerulus and in telencephalic regions including the putative medial amygdala and entopeduncular nucleus. Sustained activity outlasting the stimulus delivery was detected in regions regulating neuromodulator release, including the lateral habenula, posterior tuberculum, superior raphe, and locus coeruleus. ConclusionWe propose that these latter regions contribute to the network that defines the "threatened" state, while neurons with transient activity serve as the trigger. Our study highlights the utility of the zebrafish larval alarm response system to examine neural circuits during stress dependent brain state transitions and to discover potential therapeutic agents when such transitions are disrupted.

neuroscience↗

bioRxiv2019

Effects of mutations in pigeon Mc1r implicate an expanded plumage color patterning regulatory network

Studies in mammals have shown that the Melanocortin 1 receptor occupies a pivotal role as a nexus for integrating paracrine and autocrine signals to regulate pigment production and type-switching between pheomelanin (red/yellow) and eumelanin (black/brown) pigment synthesis in melanocytes. Inactivating mutations in the Mc1r gene are responsible for recessive pheomelanic reddening traits in several species, while mutations that increase activity cause dominant eumelanic darkening traits in mammals and birds. Previous efforts to associate Mc1r coding variants with color variation in pigeons (Columba livia) have yielded conflicting results. Applying a reverse genomic approach, we discovered a novel 500 base pair frameshifting deletion in pigeon Mc1r that likely inactivates the single-exon gene. Segregation analysis revealed complete cosegregation (LOD = 12.2) with smoky (symbol sy), a recessive pigmentation trait reported in these pages by Willard F. Hollander 80 years ago. We coupled these findings with breeding tests to determine that Dirty (V), a dominant darkening trait, is allelic to sy, and identified two independent V alleles, one of which is associated with melanic morphs of two other bird species. In contrast to observations that Mc1r inactivation results in uniform pheomelanic pelage in mammals, its loss in otherwise wild-type pigeons occurs without apparent pheomelanism, instead increasing plumage eumelanism while leaving black bar pattern elements of the tail and wing largely intact. These findings require reconsideration of Mc1rs presumed role in pigment type-switching in birds, and suggest the existence of Mc1r-independent pathways for eumelanic pigmentation pattern regulation unknown in mammals.

genetics↗

bioRxiv2019

Multispectral Imaging Differentiates Unique Macrophage Profiles in Patients with Distinct Chronic Liver Diseases

Intrahepatic macrophages influence the composition of the microenvironment, host immune response to liver injury, and development of fibrosis. Compared to stellate cells, the role of intrahepatic macrophages in the development of fibrosis remains ill defined. Multispectral imaging allows detection of multiple markers in situ in human formalin-fixed, paraffin-embedded tissue. This cutting-edge technology is ideal for analyzing human liver tissues since it allows spectral unmixing of fluorophore signals, subtraction of auto-fluorescence, and preserves architecture and the in vivo hepatic milieu. We analyzed resident Kupffer cells (CD68+), monocyte-derived macrophages (Mac387+), pro-fibrogenic macrophages (CD163+), and co-expression of pro-inflammatory (CD14) and anti-inflammatory (CD16) markers in liver biopsies from patients with hepatitis C virus (HCV) and different stages of fibrosis. Liver biopsies with advanced fibrosis showed increased accumulation of CD163+, MAC387+ and CD68+ macrophages in the portal tracts when compared to those with minimal fibrosis. Imaging software generated t-distributed stochastic neighbor embedding (t-SNE) plots and phenotype matrices that facilitated comparison of macrophage profiles. These included monocyte-derived (CD68+/Mac387+) and pro-fibrotic/anti-inflammatory (CD163+/CD16+) phenotypes. We established that the utility of this platform could be extended to liver biopsies from patients with other chronic liver diseases including nonalcoholic steatohepatitis and autoimmune hepatitis. Each disease exhibited a unique profile after spectral imaging analysis and this platform holds the potential to identify patients predisposed to progressive liver disease based on the macrophage composition. In summary, spectral imaging is a powerful tool that enables analysis of macrophage profiles in different types of chronic liver diseases and has potential to change the manner in which we evaluate liver biopsies leading to more personalized treatment strategies.

pathology↗

bioRxiv2019

Nested tandem duplications of the gene Melanoma antigen recognized by T-cells (Mlana) underlie the sexual dimorphism locus in domestic pigeons

Birds have classic examples of exaggerated sexually dimorphic traits, including colors. Sexes among the wild rock dove and its derived domestic breeds, however, are quite indistinguishable and sex can only be ascertained through genotyping or egg laying and successful hatching of eggs. Yet, the pigeon fancy has discovered sexually dimorphic traits and harnessed some of these traits in some auto-sexing breeds. Early genetics pioneers characterized the sex-linked Stipper locus and showed it to be linked to the pigeon Z linked B-locus (Tyrp1). The alleles of the Stipper locus have variable dominance relative to wild-type (more severe alleles are incompletely dominant, less severe alleles are reportedly fully dominant), characterized by a continuum of lightening in homozygotes and increased variegation in heterozygotes corresponding with severity. We leveraged this positional information and population structure among breeds in a candidate gene approach to identify the genetic mechanism of de novo pigeon sex dichromatism. A large tandem duplication (77 kb) centered on the gene Melanoma antigen recognized by T cells (Mlana) is completely associated with alleles of the Stipper locus. Copy number of the 77 kb genetic lesion was not correlated with allele severity suggesting that other mechanisms, including epigenetic regulation could underlie both allele severity and degree of variegation.

genetics↗

bioRxiv2019

Phenotyping women based on dietary macronutrients, physical activity and body weight using machine-learning tools

BackgroundNutritional phenotyping is a promising approach to achieve personalized nutrition. While conventional statistical approaches havent enabled personalizing well yet, machine-learning tools may offer solutions that havent been evaluated yet.\n\nObjectiveThe primary aim of this study was to use energy balance components - input (dietary energy intake and macronutrient composition), output (physical activity) to predict energy stores (body weight) as a way to evaluate their ability to identify potential phenotypes based on these parameters.\n\nMethodsWe obtained data from the Womens Health Initiative -Observational Study (WHI-OS) from BioLINCC. We chose dietary macronutrients - carbohydrate, protein, fats, fiber, sugars & physical activity variables - energy expended from mild, moderate and vigorous intensity activity h/wk to predict current body weight either numerically (as kg of body weight) or categorically (as BMI categories). Several machine-learning tools were used for this prediction - k-nearest neighbors (kNN), decision trees, neural networks (NN), Support Vector Machine (SVM) regressions and Random Forest. Further, predictive ability was refined using cluster analysis, in an effort to identify putative phenotypes.\n\nResultsFor the numerical predictions, kNN performed best (Mean Approximate Error (MAE) of 2.71kg, R2 of 0.92, Root mean square error (RMSE) of 4.96kg). For categorical prediction, ensemble trees (with nearest neighbor learner) performed best (93.8% accuracy). K-means cluster analysis identified 11 clusters suggestive of phenotypes, based on significantly improved predictive accuracy. Within clusters, individual macronutrient gain and loss modeling identified that some clusters were strongly predicted by dietary carbohydrate while others by dietary fat.\n\nConclusionsMachine-learning tools in nutritional epidemiology could be used to identify putative phenotypes.

epidemiology↗

bioRxiv2018

Duffy Antigen Expression in Erythroid Bone Marrow Precursor Cells of Genotypically Duffy Negative Individuals

The gene encoding the Duffy blood group protein (Fy, CD234; additional designations Duffy Antigen Receptor of Chemokines [DARC] and Atypical Chemokine Receptor 1 [ACKR1]) is characterized by a SNP in a GATA-1 transcription factor binding site associated with the erythrocyte silent (ES) phenotype. FYES homozygous people are viewed to be highly resistant to blood stage infection with Plasmodium vivax. Increasingly, however, studies are reporting P. vivax infections in Fy-negative individuals across malarious African countries where FYES approaches genetic fixation. This suggests that P. vivax has evolved a Fy-independent RBC invasion pathway, or that the GATA-1 SNP does not abolish Fy expression. Here, we tested the second hypothesis through binding studies to erythroid lineage cells using recombinant P. vivax Duffy binding protein, the parasites invasion ligand and Fy6-specific antibodies. We first observed variable Fy expression on circulating RBCs, irrespective of FY genotype; FYES RBCs were periodically Fy-positive. Furthermore, during the in vitro erythroid differentiation of CD34+ cells and on ex vivo bone marrow samples, we observed Fy expression on erythroid precursor cells from FYES people. Finally, the Fy6-specific nanobody, CA111 was used to capture Fy from the surface of FYES RBCs. Our findings reveal that the GATA-1 SNP does not fully abolish Fy expression and provide insight on potential susceptibility of Fy-negative people to vivax malaria.\n\nSignificanceDuffy blood group negativity results from a single nucleotide polymorphism (SNP) in the gene promoter, and reaches genetic fixation in many African ethnicities. Because the Duffy protein (Fy) is an important contact point during Plasmodium vivax human red blood cell invasion, Fy-negativity is considered to confer resistance to P. vivax malaria. With recent studies in African countries reporting P. vivax infection in Fy-negative people, we studied Fy expression across erythroid development. Here we report that the FY promoter SNP does not abolish Fy protein expression in erythroid progenitors developing in the bone marrow. These results further emphasizes the importance of reticulocytes as targets for P. vivax blood stage infection and propose a mechanism for P. vivax infections in Fy-negative people.

genetics↗

bioRxiv2018

Cryo-EM Structure of OSCA1.2 from Oryza sativa: Mechanical basis of hyperosmolality-gating in Plants

Sensing and responding to environmental water deficiency and osmotic stresses is essential for the growth, development and survival of plants. Recently, an osmolality-sensing ion channel called OSCA1 was discovered that functions in sensing hyperosmolality in Arabidopsis. Here, we report the cryo-EM structure and function of an ion channel from rice (Oryza sativa; OsOSCA1.2), showing how it mediates hyperosmolality sensing and ion permeability. The structure reveals a dimer; the molecular architecture of each subunit consists of eleven transmembrane helices and a cytosolic soluble domain that has homology to RNA recognition proteins. The transmembrane domain is structurally related to the TMEM16 family of calcium dependent ion channels and scramblases. The cytosolic soluble domain possesses a distinct structural feature in the form of extended intracellular helical arms that is parallel to the plasma membrane. These helical arms are well positioned to sense lateral tension on the inner leaflet of the lipid bilayer caused by changes in turgor pressure. Computational dynamic analysis suggests how this domain couples to the transmembrane portion of the molecule to open the channel. Hydrogen-deuterium exchange mass spectrometry (HDXMS) experimentally confirms the conformational dynamics of these coupled domains. The structure provides a framework to understand the structural basis of hyperosmolality sensing in an important crop plant, extends our knowledge of the anoctamin superfamily important for plants and fungi, and provides a structural mechanism for translating membrane stress to ion transport regulation.

biophysics↗

bioRxiv2018

eIF2B activator prevents neurological defects caused by a chronic Integrated Stress Response

The Integrated Stress Response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a novel eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of other disease contexts.

neuroscience↗